title: Akt activation induces hypertrophy without contractile phenotypic maturation in airway smooth muscle.
abstract: Airway smooth muscle (ASM) hypertrophy is a cardinal feature of severe asthma, but the underlying molecular mechanisms remain uncertain. Forced protein kinase B/Akt 1 activation is known to induce myocyte hypertrophy in other muscle types, and, since a number of mediators present in asthmatic airways can activate Akt signaling, we hypothesized that Akt activation could contribute to ASM hypertrophy in asthma. To test this hypothesis, we evaluated whether Akt activation occurs naturally within airway myocytes in situ, whether Akt1 activation is sufficient to cause hypertrophy of normal airway myocytes, and whether such hypertrophy is accompanied by excessive accumulation of contractile apparatus proteins (contractile phenotype maturation). Immunostains of human airway sections revealed concordant activation of Akt (reflected in Ser(473) phosphorylation) and of its downstream effector p70(S6Kinase) (reflected in Thr(389) phosphorylation) within airway muscle bundles, but there was no phosphorylation of the alternative Akt downstream target glycogen synthase kinase (GSK) 3β. Artificial overexpression of constitutively active Akt1 (by plasmid transduction or lentiviral infection) caused a progressive increase in size and protein content of cultured canine tracheal myocytes and increased p70(S6Kinase) phosphorylation but not GSK3β phosphorylation; however, constitutively active Akt1 did not cause disproportionate overaccumulation of smooth muscle (sm) α-actin and SM22. Furthermore, mRNAs encoding sm-α-actin and SM22 were reduced. These results indicate that forced Akt1 signaling causes hypertrophy of cultured airway myocytes without inducing further contractile phenotypic maturation, possibly because of opposing effects on contractile protein gene transcription and translation, and suggest that natural activation of Akt1 plays a similar role in asthmatic ASM.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Ma
authors.forename: Melanie
authors.initials: M
authors.lastname: Brown
authors.forename: Paul
authors.initials: P
authors.lastname: Kogut
authors.forename: Karina
authors.initials: K
authors.lastname: Serban
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Li
authors.forename: John
authors.initials: J
authors.lastname: McConville
authors.forename: Bohao
authors.initials: B
authors.lastname: Chen
authors.forename: J Kelley
authors.initials: JK
authors.lastname: Bentley
authors.forename: Marc B
authors.initials: MB
authors.lastname: Hershenson
authors.forename: Nickolai
authors.initials: N
authors.lastname: Dulin
authors.forename: Julian
authors.initials: J
authors.lastname: Solway
authors.forename: Blanca
authors.initials: B
authors.lastname: Camoretti-Mercado
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003285:Contractile Proteins / Q000378:metabolism; D004285:Dogs; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006984:Hypertrophy; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D014132:Trachea / Q000378:metabolism / Q000473:pathology*
chemical_list: D000199:Actins; D003285:Contractile Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038362:Glycogen Synthase Kinase 3